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101.
Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes. 相似文献
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Ohne Zusammenfassung 相似文献
105.
Xinxian Qiao Liyong Zhang Armin M Gamper Takeo Fujita Yong Wan 《Cell cycle (Georgetown, Tex.)》2010,9(19):3904-3912
Anaphase-promoting complex/cyclosome (APC/C) is a multifunctional ubiquitin-protein ligase that targets various substrates for proteolysis inside and outside of the cell cycle. The activation of APC/C is dependent on two WD-40 domain proteins, Cdc20 and Cdh1. While APC/Cdc20 principally regulates mitotic progression, APC/Cdh1 shows a broad spectrum of substrates in and beyond cell cycle. In the past several years, numerous biochemical and mouse genetic studies have greatly attracted our attention to the emerging role of APC/Cdh1 in genomic integrity, cellular differentiation and human diseases. This review will aim to summarize the recently expanded understanding of APC/Cdh1 in regulating biological function and how its dysfunction may lead to diseases.Key words: APC/C, Cdh1, proteolysis, genomic integrity, signal transduction, differentiation, tumorigenesis 相似文献
106.
Florian Full Doris Jungnickl Nina Reuter Elke Bogner Kevin Brulois Brigitte Scholz Michael Stürzl Jinjong Myoung Jae U. Jung Thomas Stamminger Armin Ensser 《PLoS pathogens》2014,10(1)
Nuclear domain 10 (ND10) components are restriction factors that inhibit herpesviral replication. Effector proteins of different herpesviruses can antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. We investigated the interplay of Kaposi''s Sarcoma-Associated Herpesvirus (KSHV) infection and cellular defense by nuclear domain 10 (ND10) components. Knock-down experiments in primary human cells show that KSHV-infection is restricted by the ND10 components PML and Sp100, but not by ATRX. After KSHV infection, ATRX is efficiently depleted and Daxx is dispersed from ND10, indicating that these two ND10 components can be antagonized by KSHV. We then identified the ORF75 tegument protein of KSHV as the viral factor that induces the disappearance of ATRX and relocalization of Daxx. ORF75 belongs to a viral protein family (viral FGARATs) that has homologous proteins in all gamma-herpesviruses. Isolated expression of ORF75 in primary cells induces a relocalization of PML and dispersal of Sp100, indicating that this viral effector protein is able to influence multiple ND10 components. Moreover, by constructing a KSHV mutant harboring a stop codon at the beginning of ORF75, we could demonstrate that ORF75 is absolutely essential for viral replication and the initiation of viral immediate-early gene expression. Using recombinant viruses either carrying Flag- or YFP-tagged variants of ORF75, we could further corroborate the role of ORF75 in the antagonization of ND10-mediated intrinsic immunity, and show that it is independent of the PML antagonist vIRF3. Members of the viral FGARAT family target different ND10 components, suggesting that the ND10 targets of viral FGARAT proteins have diversified during evolution. We assume that overcoming ND10 intrinsic defense constitutes a critical event in the replication of all herpesviruses; on the other hand, restriction of herpesviral replication by ND10 components may also promote latency as the default outcome of infection. 相似文献
107.
Nazaré M Matter H Klingler O Al-Obeidi F Schreuder H Zoller G Czech J Lorenz M Dudda A Peyman A Nestler HP Urmann M Bauer A Laux V Wehner V Will DW 《Bioorganic & medicinal chemistry letters》2004,14(11):2801-2805
A series of novel, highly potent, achiral factor Xa inhibitors based on a benzoic acid scaffold and containing a chlorophenethyl moiety directed towards the protease S1 pocket is described. A number of structural features, such as the requirements of the P1, P4 and ester-binding pocket ligands were explored with respect to inhibition of factor Xa. Compound 46 was found to be the most potent compound in a series of antithrombotic secondary assays. 相似文献
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ABCA10, a novel cholesterol-regulated ABCA6-like ABC transporter 总被引:2,自引:0,他引:2
110.
Kammerl MC Richthammer W Kurtz A Krämer BK 《American journal of physiology. Regulatory, integrative and comparative physiology》2002,282(6):R1613-R1617
Salt restriction leads to parallel increases of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys. Because the upregulation of these genes is strongly enhanced if salt restriction is combined with inhibition of the renin-angiotensin-aldosterone system, our study aimed to find out whether the juxtaglomerular expressions of renin, COX-2, and nNOS are subject to a common direct negative feedback control by ANG II. For this purpose, male Sprague-Dawley rats were fed a low-salt diet (0.02% wt/wt) with or without additional treatment with the ANG I-converting enzyme (ACE) inhibitor ramipril (10 mg x kg body wt(-1) x day(-1)) for 1 wk, and renocortical renin, COX-2, and nNOS mRNAs were assayed. To narrow down possible indirect effects of the ACE inhibitor that may result from insufficient aldosterone production, the animals received mineralocorticoid substitution with fludrocortisone (6 mg. kg body wt(-1) x day(-1)). Thus mineralocorticoid substitution prevented the fall of systolic blood pressure and of glomerular filtration induced by ramipril in rats on low-salt diet. Although fludrocortisone had no effect on basal renin, COX-2, and nNOS mRNA, it clearly attenuated the threefold increases of both renin and COX-2 mRNA in response to low-salt diet. In rats on low-salt diet, ramipril further increased renin mRNA ninefold, COX-2 mRNA fourfold, and nNOS 2.5-fold in the absence of fludrocortisone. In the presence of fludrocortisone, ramipril increased renin mRNA 10-fold, COX-2 mRNA 2.5-fold, and nNOS mRNA 2.5-fold. These data indicate that mineralocorticoid substitution lowers the overall expression of juxtaglomerular renin and COX-2 during low-salt intake and attenuates a further rise of COX-2 expression by ACE inhibition, but it does not change the stimulatory effect of ACE inhibition on renin and nNOS expression. We conclude that the expression of renin, COX-2, and nNOS in the juxtaglomerular apparatus during low-salt diet is markedly limited by a direct feedback inhibition through ANG II. 相似文献